Of the 220,900 men estimated to be diagnosed with prostate cancer in 2004 in the U.S; about one half will undergo radical prostatectomy (RP) for treatment of their disease. As many as 25% or more men who undergo this treatment will experience a re-elevation in their serum Prostate Specific Antigen (PSA) level within months to years later. This rise in PSA after prostatectomy, termed biochemical recurrence or failure, is a clear indication of the proliferation of prostate cancer cells which escaped (metastasized) prior to prostatectomy. Statistically, more than one-third of men with biochemical recurrence develop clinically detectable metastatic disease (Pound 1999). This non-curable, lethal stage of prostate cancer claims over 29,000 lives in the U.S. annually. Clinicians are unable to predict with certainty which men are likely to fail therapy and subsequently develop metastatic disease and which are not. We hypothesize that the likelihood of disease recurrence after treatment of prostate cancer by RP is modified and/or determined by sequence variation in genes that regulate prostate cancer metastasis. Restating this hypothesis, genetic background is a determinant of metastatic potential. The Specific Aims of this application are: 1) Explore the association between genetic variants in metastasis-related genes and disease progression in a case-control population of men who have undergone radical prostatectomy for treatment of clinically localized prostate cancer; cases are men whose disease progressed after surgical therapy, and controls are men whose disease did not progress; 2) For genes demonstrating association with progression in Specific Aim 1, confirm the association in a second, similar case-control population; 3) For genes associated in both populations, perform fine-mapping association tests, and assess association in non-European Americans cases; 4) Assess genotype - phenotype correlation for progression associated genes. We anticipate that this study will provide novel insights into the mechanisms responsible for prostate cancer progression, and provide a basis for the identification of men at elevated risk for this life threatening event.